Our encompassing objective is an integrated, comparative study of critical changes in structure and metabolism of cells aging in culture and of tissues of aging animals. In studies with cells we shall use WI-38 human lung fibroblasts, human uterine and skin fibroblasts, and animal aorta smooth muscle cells. Because changes in cellular events may be initiated in the cell membrane, we shall study the composition, antigenic characters and metabolic activities of the membranes of cells aging in culture. This will include flux of lipids between medium and membrane, turnover and regeneration of glycoproteins of membrane, and transport of sugars and amino acids. We shall examine hormone-receptor interactions and their relation to levels and metabolism of cAMP and cGMP. Selected mitochondrial membrane properties will be studied, including transport of glutamate and other amino acids and associated translocation of cations such as calcium. Because collagen synthesis is a main function of fibroblasts, we shall study intensively, in relation to aging, the regulation of collagen synthesis and its post-translational modifications, including hydroxylation and glycosylation. Accordingly, changes with age of proline synthesis, incorporation, hydroxylation will be studied, as well as nature of proline tRNAs. We shall study the effect of oxygen levels on hydroxylation of collagen in parallel with hydroxylation of butyrobetaine to carnitine, since the relevant dioxygenases are similar. The possible control of collagen metabolism by hormones, prostaglandins and cyclic nucleotides will be studied in various fibroblasts. Glucocorticoids known to prolong the life-span of Wl-38 cells will be studied for changes in forming complexes with cytosol proteins, and the transfer of the complex to the nucleus and effects on RNA synthesis also studied in relation to aging. In whole animals as in cells we shall study changes with age of sensitivities to hormone response. We shall seek an order and connection among events in a culture that is aging, and try to determine fundamental changes in regulation that are associated with aging; and we shall study whether the regulatory events are programmed.